Summary Acute ischemic injury, such as myocardial infarction (MI), is a major contributor toward the development of heart failure (HF), a progressive disease affecting millions of patients and costing billions of dollars annually. Leukocytes are rapidly recruited to the heart after ischemic injury where they regulate a wide variety of responses including cardiomyocyte survival, fibrosis, infarct stabilization and revascularization. Initially, inflammatory and phagocytic leukocytes are recruited to degrade dead cells and damaged matrix, followed by reparative leukocytes to stabilize the myocardium and resolve the injury. As such, modulation of the balance between leukocyte-dependent inflammation and resolution processes within the heart after ischemic injury is at the forefront of recent efforts to diminish prolonged adverse post-ischemic remodeling and persistent inflammation associated with chronic HF. The sympathetic nervous system can influence leukocyte processes, in part via stimulation of ?-adrenergic receptor (?AR) signaling, and becomes activated after cardiac injury. We recently showed that, compared to normal mice, chimeric mice lacking ?2AR expression in cells of hematopoietic origin (?2ARKO BMT mice) displayed 100% mortality via cardiac rupture following MI, which was associated with decreased leukocyte recruitment to the heart. Mechanistically, we have demonstrated that ?2AR acts in a signaling pathway-biased manner to regulate leukocyte responses to cardiac injury via G protein coupled receptor kinase (GRK)/?-arrestin (?arr)-dependent ?2AR signaling. Arising from this work are questions related to the extent to which ?2AR signaling regulates inflammatory versus reparative leukocyte populations and their survival following cardiac injury, and whether biased ?2AR signaling offers a novel approach to regulate these processes to improve cardiac remodeling outcomes. Further, since ?2AR deletion negatively regulates leukocyte functions, the possibility exists that clinically used ?-blockers may similarly impact leukocyte responsiveness to ischemic injury and survival within the injured myocardium. Therefore, we aim to 1) define the ?2AR expression-dependent alterations in leukocyte survival following acute cardiac injury, 2) evaluate the impact of ?-blocker treatment on mouse and human leukocyte function and survival, and 3) differentiate the effects of leukocyte-specific biased ?2AR signaling on cardiac remodeling and survival following injury. Overall, we will attain a fundamental understanding of the mechanisms and influence of ?2AR signaling on the early immune response to cardiac injury and determine whether ?2AR-selective therapeutics would offer fine-tuned strategies to regulate ischemic injury-induced remodeling and survival outcomes.